Professional Documents
Culture Documents
June 2009
AGOMELATINE
Summary
Contents
The drug and the review
Summary 1
Background 5 • Agomelatine is a new antidepressant with selective agonist actions at mela-
Safety 6 tonin receptors and selective antagonist action at serotonin 5HT-2C recep-
Efficacy studies 7 tors. It does not affect the uptake of serotonin, noradrenaline or dopa-
Short term studies 9 mine.
Short term studies with • Agomelatine was launched in the UK in June 2009.
active controls 12
Long term/ prevention
• This review evaluates the evidence supporting agomelatine use in adults
of relapse 13 with major depressive episodes and seeks to define agomelatine’s potential
Absence of discontinuation place in therapy.
symptoms 14
Sexual dysfunction 15 Background
Sleep disorders 17 • NICE Guidance (2004 and draft update 2009) recommends an SSRI antide-
Rating scales and Sleep
pressant (e.g. generic fluoxetine or citalopram) first-line for patients with
assessments 19
Cost per 100,000 moderate to severe depression.
population 20 • Following first-line treatment failure the evidence for sequencing antide-
References 21 pressants is inconclusive, choice should therefore be based on the needs of
Appendices 24 the patient, the profile of the drug and financial considerations.
• New NICE Guidelines on the treatment of depression in adults are antici-
pated in September 2009.
Literature searched
Produced for the • We searched: Medline (agomelatine.af [Limit to: Humans and English Lan-
London New Drugs Group guage]); Embase (agomelatine.af [Limit to: Human and English Language]
by: and [DEPRESSION/dt [Drug Therapy] or *MAJOR DEPRESSION/dt [Drug
Therapy]]); and IDIS ("AGOMELATINE 28160472").
Alexandra Denby,
Regional MI Manager • This was supplemented with information from the EMEA website (Public
Medicines Information Service Assessment Report), NICE guidance, and contact with the manufacturer
Northwick Park Hospital Servier Laboratories.
Middlesex • The study programme was extensive:
HA1 3UJ • 1 short-term placebo-controlled dose ranging study (8 weeks)
Tel: 020 8869 3551 • 2 short-term placebo-controlled studies (6 weeks with optional exten-
Med.info@nwlh.nhs.uk sion for a further 46 weeks)
Further copies of this document • 3 short –term placebo-controlled studies with paroxetine or fluoxetine
are available from URL: active controls (6 weeks and optional extension to 6 months)
www.nelm.nhs.uk
• 2 long-term relapse prevention studies.
• 1 study vs. venlafaxine (6 weeks with optional extension to 6 months),
primary endpoint sleep, secondary endpoint efficacy
• 1 study vs. venlafaxine (12 weeks with optional extension to 6
months), primary endpoint sexual function, secondary endpoint effi-
cacy
• 1 study vs. sertraline (6 weeks with extension to 6 months), primary endpoint actigraphy,
secondary endpoint efficacy
• 1 open study in patients with major depressive disorder (6 weeks) looking at the effect on
sleep EEG
• 1 study vs. fluoxetine in patients with severe depression (8 weeks with optional extension to
6 months)
• 1 study on sexual disturbance vs. paroxetine.
Efficacy studies
• Antidepressant efficacy is generally determined from 6–8 week RCTs comparing response
against placebo or active comparators, or 6–10 month RCTs comparing relapse rate against pla-
cebo; depression symptoms are evaluated using rating scales.
• All analyses were carried out in the intention-to-treat populations: i.e. analysis was performed
according to the assigned treatment group regardless of protocol deviations and participant
compliance or withdrawal.
Short-term placebo-controlled
• A dose-ranging study (n=711) identified agomelatine 25mg daily as the target dose when com-
pared with agomelatine 1mg and 5mg daily
• In two 6 week placebo controlled RCTs patients with a HAMD score ≥ 22 [moderate to severe
depression] were randomised to either agomelatine (25mg initial for 2 weeks increased to
50mg in non-responders) or placebo; primary endpoint was mean final HAMD score.
• In the first study, 212 patients received agomelatine (n=106) or placebo (n=105). For
the ITT population the between group difference for the mean final HAMD scores was
2.30 (S.E. 1.02), p=0.026.
• In the second study, 238 patients received agomelatine (n=118) or placebo (n=120).
For the ITT population the between group difference for the mean final HAMD scores was
3.44 (S.E. 0.92), p<0.001
• 3 unpublished placebo-controlled studies in which paroxetine or fluoxetine were used as active
controls to validate the study design are reported in the EMEA public assessment report (EPAR).
The efficacy of agomelatine was not directly compared to that of the active controls.
• All 3 studies enrolled patients with moderate to severe depression [HAMD ≥ 22] and fol-
lowed similar methodologies: initial run-in followed by randomisation to agomelatine,
placebo, or active control for 6 weeks with subsequent 18 week extensions.
• The option to increase the agomelatine dose from 25mg to 50mg was not included in
these studies.
• The primary endpoint of difference in HAMD was compared between active control and
placebo, and between agomelatine and placebo. For the first trial, a statistically signifi-
cant difference (p=0.008) was seen between active control and placebo at 6 weeks for
reduction in HAMD score versus placebo, but not for agomelatine and placebo; Neither
the second nor third trial showed statistically significant differences between agomelatine
or the active control and placebo for any comparison at either 6 or 24 weeks, meaning
that no discernable results could be drawn from these studies. A meta-analysis of
agomelatine trials shows that 23.5% of patients require a 50mg dose, which is a reason
why agomelatine may have failed to differentiate from placebo in the first study. The
second and third studies were associated with high placebo response rates.
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• In the 12 week study patients were randomised to agomelatine 50mg (n=137) or venla-
faxine 150mg (n=140). The primary endpoint of the study was deterioration in sexual func-
tion and demonstrated statistically significant differences in favour of agomelatine versus
venlafaxine. For the secondary endpoint of the final MADRS score, agomelatine was shown
to be at least as effective as venlafaxine (10.1 vs. 9.8).
• In the 6 week study patients were randomised to either agomelatine (n=165) or venlafaxine
(n=167). The primary endpoint was the effects on sleep variables and demonstrated statis-
tically significant differences in favour of agomelatine versus venlafaxine; final HAMD score
was the secondary endpoint. The final HAMD scores were similar between the groups, indi-
cating similar efficacy for agomelatine and venlafaxine (9.9 vs. 11.0).
• A 8 week study randomised 500 outpatients with HAMD score ≥25 and CGI severity of illness score
≥4 (severely depressed) to agomelatine 25-50mg (n=247) or fluoxetine 20-40mg (n=257) [for
agomelatine the initial lower dose was increased at 2 weeks in non-improved patients, for fluoxet-
ine the initial lower dose was increased at 4 weeks]. The primary endpoint was improvement in
HAMD score from baseline, the difference in scores at week 8 was 1.49, 95% CI=[0.20;2.77]
(p=0.024) in favour of agomelatine.
Long-term relapse-prevention
• Relapse is classified as the appearance of the symptoms of the index episode soon after medica-
tion is stopped, whilst recurrence is the appearance of symptoms in a new episode. Relapse indi-
cates that the treatment duration was too short.
• A study reported in the EPAR had an 8-week open label phase (n=610) during which response to
agomelatine was determined, followed by a 26-week double-blind randomised phase (n=367;
agomelatine 25mg, n=187; placebo, n=180).
• At the end of the 26 week double-blind phase, a significant effect was not demonstrated for
the primary endpoint of relapse (agomelatine 25.9% vs. placebo 23.5%). The placebo re-
lapse rate in this trial was unexpectedly low (approximately half that seen in other studies of
similar design). This may be reflective of some methodological aspects e.g. the broad range
of the severity of depression of patients at inclusion.
• 169 severely depressed patients (n=89 agomelatine, n=80 placebo) (HAMD >25 and CGI-S
≥5) continued in an 18 week extension; at the end of this extension there was a statistically
significant difference in favour of agomelatine (21.3% vs. 31.3%) p=0.046.
• A second (published) study, that included a high proportion of patients with moderate to severe
depression reflecting the types of patient generally seen by psychiatrists, had an 8-10 week open-
label dose determination phase (n=492) followed by a 24 week double-blind phase (n=390)
• For the primary endpoint of relapse, results at 24 weeks were significantly lower (p=0.0001)
for agomelatine (21.7%) than for placebo (46.6%); agomelatine reduced relapse risk by
54% (HR 0.458; 95% CI 0.305–0.60).
• 190 patients (n=106 agomelatine, n=84 placebo) continued in double-blind 20 week exten-
sion. A statistically significant difference in the time to relapse was detected: at 10 months
twice as many patients treated with placebo relapsed (49.9%) compared to those treated
with agomelatine (23.9%) (p<0.0001).
• The three short term studies with active controls all had 18 week extensions. In one study the
relapse rates were lower with agomelatine (14.3%) and fluoxetine (17.8%) than with placebo
(33.3%), p=0.017 and p=0.045 respectively. In the other 2 studies there were no differences
seen between agomelatine or active control and placebo which means no discernable results could
be drawn.
Safety
• Agomelatine does not cause weight gain, has a low risk of sexual dysfunction, low incidence of
gastro-intestinal reactions, absence of discontinuation symptoms, no sedation or daytime drowsi-
ness and an overall incidence rate of adverse events that is similar to placebo.
• Emergent elevations of liver transaminase enzymes more than 3x upper limit of normal (3x ULN)
occur rarely (approx. 1% of patients). Overall incidences of elevations >3xULN in all patients (i.e.
regardless of their transaminase values at baseline) were 1.1% with agomelatine 25mg and
0.72% with placebo (p=not significant). The 0.4% absolute difference with placebo compares to a
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• Overall, the data demonstrate a potential role for agomelatine in treating adults with major de-
pressive disorder. The efficacy studies suggest comparable efficacy to currently licensed antide-
pressants.
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Health economics
• No health economic studies of agomelatine have been published.
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should be repeated within 48 hours. Therapy patients assigned to placebo will respond within
should be discontinued if the increase exceeds six weeks.4
3xULN and liver function tests should be per-
formed regularly until they return to normal.2 If The problem for the evaluation of antidepres-
any patient develops symptoms which suggest sants is that the study population is likely to de-
hepatic dysfunction, LFTs should be carried out termine the magnitude of the treatment benefit.
and the decision to continue therapy should be a A poorly selected study population will make a
clinical one, based on laboratory evaluations. If drug look bad; a well selected study population
jaundice develops, treatment must be stopped. will make a drug look better. Since treatment of
Agomelatine should be used with caution in pa- real patients is not subject to the perverse in-
tients who consume a large quantity of alcohol or centives of drug trials, it is often assumed that
who are treated with other drugs that may cause trials that recruit a more severe study popula-
hepatic damage.2 tion corresponds better to everyday practice
than trials that do not. The existence of poorly
Agomelatine is metabolised mainly by cytochrome conducted trials showing minimal benefits can-
P450 1A2 (CYP1A2) (90%) and by CYP2C9 not be ignored, however, and has been used to
(10%). Treatment with agomelatine is contra- case doubt on the efficacy of antidepressants as
indicated in patients who are also taking potent a class.
CYP1A2 inhibitors, such as fluvoxamine and cipro-
floxacin as they can increase the serum levels of Efficacy studies
agomelatine. Use of moderate CYP1A2 inhibitors,
such as oestrogens and propranolol with agome- A number of studies have been carried out as-
latine should be with caution until more experi- sessing the efficacy and safety of agomelatine.
ence has been gained.2 Agomelatine does not These are described in detail in this review, and
induce CYP450 isoenzymes and will not modify their design and main results are summarised in
exposure to medicinal products metabolised by Appendix 1. All patients enrolled had moderate
CYP450.2 to severe depression. The study programme
was extensive:
The placebo response
• 1 short-term placebo-controlled dose ranging
Over the years there has been an increase in the study (8 weeks)7
percentage of patients responding in the placebo • 2 short-term placebo-controlled studies (6
arms of published studies of major depression.3 weeks with optional extension for a further
There have been no studies comparing placebo 46 weeks)8;9
with no treatment in depression, so these patients • 3 short –term placebo-controlled studies
represent several different kinds of treatment ef- with paroxetine or fluoxetine active controls
fect, such as patients who may have had their (6 weeks and optional extension to 6
depression scores inflated to ensure study entry, months)6
patients who were accurately rated but show an
• 2 long-term relapse prevention studies6;10;11
early spontaneous remission and true responders
to placebo.3 The difference in improvements in
• 1 study vs. venlafaxine (6 weeks with op-
depressive symptoms between the drug and the tional extension to 6 months), primary end-
placebo is thought to be greater with increasing point sleep, secondary endpoint efficacy12
degrees of severity of depression. This is often • 1 study vs. venlafaxine (12 weeks with op-
difficult to demonstrate as data is quoted for en- tional extension to 6 months), primary end-
tire groups, rather than individual patients and point sexual function, secondary endpoint
the distribution of the depression rating scores efficacy13
can overlap, thereby diluting the effect.3 • 1 study vs. sertraline (6 weeks with exten-
sion to 6 months), primary endpoint actigra-
Use of a placebo in an antidepressant trial does phy, secondary endpoint efficacy14;15
not necessarily mean that the patient is un- • 1 open study in patients with major depres-
treated.4 Patients will have regular visits to their sive disorder (6 weeks) looking at the effect
doctor, supportive help and interest in their wel- on sleep EEG16
fare. In some trials they will be able to contact • 1 study vs. fluoxetine in patients with severe
the therapist when they need to. Patients in the depression (8 weeks with optional extension
placebo arm will receive everything apart from to 6 months) (conference abstract only)
the active drug, and this can constitute a treat- • 1 study on sexual disturbance vs. paroxeti-
ment in itself. It has been estimated that 30% of ne18
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June 2009
Agomelatine
Study Primary
Treatment Results Comments
design endpoint
• HAMD scores:
• at endpoint (overall ITT
HAMD final population): 14.1, agome-
score (ITT latine, 16.5 vs. placebo;
Agomelatine
population) • The mean baseline HAMD score was 26. The dose was
25-50mg difference 2.4, p=0.026.
Secondary increased in 36 patients in the agomelatine group and
daily • Group whose dose was in-
efficacy vari- 38 in the placebo group. Seven out of the 12 in the
(n=106) or creased at wk 2: 17.5,
6-week ran- ables: re- placebo group who discontinued did so because of lack
placebo agomelatine vs. 20.4 pla-
domised, sponse to of efficacy, compared to two out of the seven in the
(n=105). cebo; difference 2.9,
double- treatment agomelatine group who discontinued.
Agomelatine p=0.045.
blind study (≥50% re- • The difference in HAMD scores in the overall population
dose in- • severe depression: 14.4,
in adults duction in is below that defined by NICE as clinically significant.
creased to agomelatine vs. 17.3, pla-
with HAMD HAMD score), Results are detailed further in Appendix 1.
50mg after 2 cebo; difference 2.9,
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score ≥22.8 time to first • Dizziness, nasopharyngitis and influenza were more
weeks in p=0.024).
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response, common in the agomelatine group, whilst headache,
non- • Response rates: 49.1%,
CGI-Severity nausea, fatigue, dry mouth and diarrhoea were more
improved agomelatine vs. 34.3%, pla-
and CGI- common in the placebo group.
patients cebo, p=0.03.
Improvement
scores. • Remission rates: 20.8%,
agomelatine vs. 13.3%, pla-
cebo.
June 2009
HAMD final
At week two, 28 (25.2%) of patients taking agome-
score (ITT
Agomelatine
Double-
• HAMD final scores: 11.1,
blind, ran-
agomelatine vs. 12.7, • This study has not yet been fully published and there-
domised, 8 Agomelatine
fluoxetine. fore cannot be fully evaluated: information comes
week study 25-50mg Change in
• Change in HAMD score: - from the World Psychiatric Association conference,
in patients (n=247) or HAMD score
17.3, agomelatine, -16.0, April 2009.
with HAMD fluoxetine from base-
fluoxetine. • Doses were increased after 2 weeks (agomelatine) or
score ≥25 & 20-40mg line.
• Between-group difference: 4 weeks (fluoxetine) in non-improved patients.
CGI severity (n=257).
illness score 1.46, p=0.024 in favour of • Patients enrolled in this trial had severe depression.
≥4.17 agomelatine.
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domised, 50-100mg • Responder rates: 70% after six weeks of treatment.
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Secondary
double-blind (n=159). agomelatine vs. 61.5% ser- • Most commonly reported adverse events were dry
endpoint:
study in Doses were traline, p=0.119. mouth, headache, diarrhoea and fatigue. More pa-
change in
adults with increased • Between-group difference tients discontinued sertraline (11.3%) than agome-
HAMD score
HAMD score after 2 for CGI-S: 0.28, p=0.043. latine (2.6%).
from base-
≥22.14;15 weeks in • Between-group difference • See Sleep Disorders section for primary endpoint
line of ≥50
non- for CGI-I: 0.29, p=0.023. data.
in ITT popu-
June 2009
Treatment Results Comments
design endpoint
Agomelatine
Double-
blind, ran-
• There was no significant difference between the treat-
domised 12
ments in the treatment of depression, as shown by the
week study Change in
• MADRS final score: 10.1, reduction in MADRS score and CGI-S and CGI-I score
comparing sexual func-
agomelatine vs. 9.8 venla- changes from baseline. Similar percentages of patients
the sexual Agomelatine tion.
faxine. were responders and remitters in both groups.
side effects 50mg
• Responder rates: 82.5% • 38.1% of patients on venlafaxine had adverse events vs.
of agome- (n=137) or Secondary
agomelatine vs. 79.9% 20.4% on agomelatine. Nausea, headache and upper
latine and venlafaxine endpoint:
venlafaxine. respiratory tract infections were the more common in
venlafaxine 150mg antidepres-
• Remitter rates: 73% both groups. More patients discontinued venlafaxine
in adults (n=140). sant efficacy
agomelatine vs. 66.9% (8.6%, mainly because of gastrointestinal or central
with moder- and toler-
venlafaxine. nervous system side effects) than agomelatine (2.2%).
ate depres- ability
sion • See Sexual dysfunction section for primary endpoint
(MADRS data.
≥20).13
• Agomelatine was as effective as venlafaxine in treating
Agomelatine • HAMD final scores: 9.9 ± depression, in both the overall population and the se-
25mg 6.6, agomelatine vs. 11.0 verely depressed patients.
Random- (n=165) or ± 7.4 venlafaxine. Be-
Leeds Sleep • The time course of improvements in the HAMD score
ised, dou- venlafaxine tween-group difference of
Evaluation was similar for each treatment group and there was no
ble-blind 6 75mg 1.1.
Question- significant difference between the groups at any study
week study (n=167). • Response rates: 76.4%
naire ‘getting visit.
comparing Doses were agomelatine vs. 70.6%
to sleep After an additional 18 weeks more patients taking agome-
the effects increased venlafaxine.
score’ latine (71.6%) compared with those taking venlafaxine
of agome- after 2
• CGI global improvement (66.7%) were still in remission. Bias from the initial fo-
latine and weeks in
Secondary final scores: 1.6±0.7, cus on subjective sleep parameters in favour of agome-
venlafaxine non-
endpoint: agomelatine vs. 1.6±0.8, latine cannot be ruled out. 6
on subject improved
venlafaxine. • Nausea, dizziness and vomiting were more common with
sleep vari- patients
Changes in • venlafaxine than with agomelatine (22.6% vs. 6.0%;
ables. Pa-
HAMD-17 • Severely depressed pa- 9.5% vs. 1.8% and 4.8% vs. 1.2% respectively). Sero-
tients had Patients
score and tients: tonin syndrome occurred in 3% of patients on venla-
HAMD score could con-
CGI- • HAMD final scores: faxine. More patients withdrew due to adverse events in
≥20.12 tinue with an
18-week ex- 11.2±7.0, agomelatine vs. the venlafaxine group (13.2%) vs. the agomelatine
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tension.6 11.2±6.9, venlafaxine. group (4.2%).
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• See Sleep Disorders section for primary endpoint data.
Hamilton Depression Rating Scale (HAMD) score ≥22 = DSM-IV criteria for major depressive disorder (moderate or severe)
Response to treatment = ≥50% reduction in HAMD score.
Intention-to-treat population: ITT
June 2009
Agomelatine
Study Primary
Treatment Results Comments
design endpoint
• HAMD final score: 14.5±8.2 agomelatine vs. 15.9±
8.6 placebo (not statistically significantly different,
NS). • After six weeks of treatment,
• HAMD final score in fluoxetine group was 2.59 points agomelatine 25mg was not
lower than in the placebo group (p=0.008). significantly better than pla-
Randomised, Agomelatine
cebo in treating depression
double-blind 25mg (n=133) • Responders: 53% agomelatine vs. 47% placebo
but fluoxetine was signifi-
6 week study or fluoxetine (p=NS); 58% fluoxetine vs. 47% placebo (p=NS).
cantly better than placebo.
in adults with 20mg (n=137)
HAMD score or placebo • At the end of the 18 week
• After 18 week extension:
≥22.6 (n=149) extension the rate of relapse
• HAMD: 10.0, agomelatine, 10.7 placebo, 8.4 fluoxet- was significantly lower with
ine. agomelatine (and fluoxetine)
HAMD score • Relapses: 14.3% agomelatine, 33.3% placebo, 17.8% than with placebo.
fluoxetine, (p=0.017 agomelatine vs. placebo;
Secondary p=0.045 fluoxetine vs. placebo).
variables in- • HAMD final score: 13.0±8.0 agomelatine vs. 13.8±8.0 • Agomelatine was not more
cluded CGI, placebo (p=NS). efficacious than placebo after
Randomised, Agomelatine Hamilton Anxi- • HAMD final score in paroxetine group 12.2±8.1. p= six and 18 weeks of treat-
double-blind 25mg (n=142) ety Rating NS vs. placebo. ment.
6 week study or paroxetine Scale, Leeds • Response to treatment and time to remission. • Paroxetine (active control)
in adults with 20mg (n=138) Sleep Evalua- was also not significantly bet-
HAMD score or placebo tion Question- • After 18 week extension: ter than placebo at either
≥22.6 (n=137). naire. • No statistically significant differences in the rates of time point.
relapse and loss of first response when comparing • No discernable results can be
agomelatine or paroxetine with placebo. drawn from the study
• HAMD final score: 12.0±8.2 agomelatine vs. 13.4±8.4 • Agomelatine was not more
Agomelatine placebo (p=NS). efficacious than placebo af-
Randomised, 25mg (n=150)
• HAMD final in fluoxetine group was 0.53 lower than in ter six and 18 weeks of
double-blind or 50mg
the placebo group (p=NS). treatment.
6 week study (n=151) or
• Fluoxetine was also not sig-
in adults with fluoxetine
• After 18 week extension: nificantly better than pla-
HAMD score 20mg (n=148)
• No statistically significant differences in the rates of cebo at either time point.
≥22.6 or placebo
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(n=158). relapse and loss of first response when comparing • No discernable results can
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agomelatine or fluoxetine with placebo. be drawn from the study
• The option to increase the agomelatine dose from 25mg to 50mg was not included in these studies so some patients may not have been
adequately treated. A meta-analysis of agomelatine trials shows that 23.5% of patients require a 50mg dose, which is a reason why agome-
latine failed to differentiate from placebo.
• About 50-60% of placebo-controlled efficacy studies fail to show a superior efficacy of the antidepressant used to validate the study popula-
tion. One reason for this is the inclusion of patients with insufficient severity, making it difficult to demonstrate a statistically significant
June 2009
response. Relapse is classified as the appearance of the symptoms of
the index episode soon after medication is stopped, whilst recurrence
Agomelatine
Primary
Study design Treatment Results Comments
endpoint
HAMD total • Relapse rates: 25.9%, agome-
Agomelatine score W0 latine vs. 23.5%, placebo, p = • No relapse-preventing effect was demonstrated.
25mg for 8 to W8, time not significant. No statistically significant difference in HAMD total
8 week open weeks then, in to relapse • scores between the two groups was seen.
label followed patients with after week • Relapse rates in a post-hoc • Similar results in both groups for the secondary
by a 26 weeks HAMD ≤10, 8 defined analysis (pts with more severe endpoints, measuring severity of illness and im-
double-blind, agomelatine as HAMD depression,46% of the total trial provements in the condition, were seen.
randomised 25mg (n=187) ≥16 or sui- population): 21.3%, agome- • The relapse rate in the placebo arm was unexpect-
phase.6 or placebo cide/suicide latine vs. 31.3% placebo. The edly low and may reflect some of the methodologi-
(n=180) for attempt difference became statistically cal aspects, such as the broad range of the severity
26 weeks. (ITT popu- significant at week 52 of depression of patients included in the study.
lation) (p=0.046).
Agomelatine
25-50mg for • At 24 weeks: • Baseline characteristics of the two treatment
8-10 weeks • Relapse rates: 21.7%, agome- groups were similar. The patients were on aver-
then, in pa- latine vs. 46.6%, placebo, age 43.3 years old, with ~3.6 prior depressive epi-
tients with p<0.0001. sodes, and over 70% were female. The mean
HAMD ≤10, • Risk of relapse reduced by 54% HAMD17 total score at the beginning of the open-
8-10 week Relapse, (hazard ratio 0.458, 95% CI
agomelatine label period was 27 and the mean GCI-S score was
open label defined as 0.305 to 0.60).
25mg 4.9; by the start of the double-blind phase these
study followed HAMD ≥16
(n=141), • Depressive relapse: 20.6%, had fallen to 6 and 1.8 respectively, indicating that
by a 24 week or any
50mg (n=24) agomelatine vs. 41.4%, pla- 8-10 weeks of agomelatine open-label treatment
double-blind, withdrawal
or placebo cebo. had improved depressive symptoms.
randomised, for lack of
(n=174) for • Cumulative relapses: 22.7%, • 390 patients of the 492 originally enrolled entered
phase. Adults efficacy or
24 weeks. agomelatine vs. 50.4%, pla- the 24-week double-blind phase.
enrolled if they suicide/
had HAMD suicide at- cebo, p<0.0001. • Three patients discontinued due to lack of efficacy,
190 pts • all in the agomelatine group. Adverse events were
≥22 and CGI- tempt (ITT
(agomelatine • After a further 20 weeks24 the reason for discontinuation in 4 patients on
S ≥4.10;11 population)
106 and pla- agomelatine compared with one taking placebo.
• Relapse: 23.9%, agomelatine
cebo 84) con- The most commonly reported adverse events were
vs. 49.9%, placebo, p<0.0001.
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tinued with a headache (10.3% in the agomelatine group and
In the more severely depressed
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further 20 7.5% in the placebo group), nasopharyngitis (6%
patients, this risk was reduced
weeks of vs. 9.8%) and back pain (6.1% vs. 3.4%).
by 58.6% (p<0.0001).
treatment.
Hamilton Depression Rating Scale (HAMD) score ≥22 = DSM-IV criteria for major depressive disorder (moderate or severe).
There is one fundamental difference between the two trials. In the second trial, a larger proportion of patients had severe depression (80%
vs. 46%). The results of the second trial were accepted by the CHMP as a demonstration of maintenance of efficacy, probably because of
June 2009
Agomelatine
All antidepressants have the potential to cause withdrawal symp- Symptoms include nausea, vomiting, headaches, loss of appetite,
toms. The Maudsley Prescribing Guidelines recommend that when agitation, sweating, worsening of symptoms and weakness. These
one has been taken for 6 weeks or longer, it should not be usually occur within the first few days of discontinuing treatment
stopped abruptly unless a serious adverse event has occured.18 and are generally mild to moderate, but in some patients may be
severe.26
Primary
Study design Treatment Results Comments
endpoint
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DESS: Discontinuation Emergent Signs and Symptoms check list, a clinician rated instrument which covers 43 signs and symptoms
associated with discontinuation or interruption of antidepressant treatment. The limitation to the DESS is that some symptoms could
occur even if no discontinuation has taken place.
June 2009
Sexual dysfunction is a side effect that has been attributed to antide- therapy. The effects of dopamine and noradrenaline on sexual func-
Agomelatine
pressant use, and can be problematic, especially leading to problems tioning could explain the diminished feelings of desire and arousal
with long-term treatment compliance.29 About one third of patients experienced by patients with depression. Dopamine influences de-
(36%) find antidepressant-induced sexual dysfunction to be an unac- sire and motivates sexual behaviour, whilst noradrenaline stimulates
ceptable side effect, constituting grounds for discontinuation of arousal. Serotonin systems have a negative effect on arousal.27
Primary
Study design Treatment Results Comments
endpoint
Percentage of SAR population
with: • The differences were maintained when the re-
• Deterioration in total scores: sults were analysed separately for men and
7.3% agomelatine vs. 15.7% women (but note the small number of men in the
venlafaxine. trial). Treatment-emergent sexual dysfunction
• Reduced sex drive/desire: was significantly less prevalent among sexually-
Percentage
3.6% agomelatine vs. 19.4% active patients who received agomelatine com-
Double-blind, of patients
venlafaxine, p=0.007. pared with venlafaxine. The main differences
randomised in the SAR
were in reduced desire and orgasm, which re-
12 weeks group re- • Deterioration in orgasm in
flects the pharmacological differences between
study com- porting a women: 4.3% agomelatine
the two treatments. Venlafaxine inhibits
paring the Agome- deteriora- vs. 21.2% venlafaxine,
noradrenaline, dopamine and serotonin, whilst
sexual side latine tion of at p<0.0001.
agomelatine is a melatonin agonist and also in-
effects of 50mg least one • Trend towards more favour-
creases noradrenaline and dopamine. It should
agomelatine (n=137) or point from able scores with agomelatine
be noted that, as for other antidepressant trials,
and venla- venlafaxine baseline in with other domain and total
no sexually related adverse events were re-
faxine in 150mg the Sex FX scores.
corded, but instead they were reported via indi-
adults with (n=140). scale.
rect questioning.
moderate de- Percentage of SA-FS population
•38.1% of patients on venlafaxine had adverse
pression Secondary with deterioration in:
events vs. 20.4% on agomelatine. Nausea, head-
(MADRS endpoint: • Desire: 6% agomelatine vs.
ache and upper respiratory tract infections were
≥20).13 changes in 16.4% venlafaxine.
the more common in both groups. More patients
depression. • Orgasm: 9.1% agomelatine discontinued venlafaxine (8.6%, mainly because
vs. 18.5% venlafaxine of gastrointestinal or central nervous system side
• Total Sex FX score: 8.2% effects) than agomelatine (2.2%).
agomelatine vs. 15.2% venla- •Seen Short Term studies section for data on de-
faxine. pression.
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• P<0.0001 for all.
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Assessments used: Sex FX scale to assess sexual function (the first 11 out of the 13 item scale address three domains: desire, arousal
and orgasm, whilst the last two items provide a measure of global satisfaction). MADRS, CGI-S and CGI-I scales to assess depression.
SAR: sexually active remitters group: agomelatine n=60 (14 male), venlafaxine n=51 (18 male). Patients in this group had a decrease
at week 10 of 50% or more in sexual activity from baseline and a f
inal MADRS score of ≤12.
SA-FS : sexually active full set – all subjects sexually active at baseline; agomelatine n=103, venlafaxine n=90.
June 2009
Sexual Acceptability Set (n=87):
Agomelatine
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PRSEXDQ-SALSEX: Psychotrophic-related sexual dysfunction questionnaire. 7 items on sexual function. Sexual dysfunction (SD) was de-
fined as at least one impairment in one of the following four items: decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejacula-
tion (score of ≥1 for each of these three) and erectile dysfunction (score of ≥2). Score 0 = no sexual dysfunction, 15 = maximum sexual
dysfunction. For each item 0=nil or never, 3 = severe or always.
Sexual Acceptability Set: all volunteers having a sexual dysfunction assessment after at least 2 weeks and compliant to the treatment.
June 2009
sleep spindles and K-complex waves appear during the onset of the deeper tivity.29
Agomelatine
sleep of stage 2 and stages 3 and 4 (deepest sleep) are defined by desyn-
chronised slow (delta) waves.29
Study Primary
Treatment Results Comments
design endpoint
• Total sleep time increased from 363±60 • At baseline 11 patients reported difficulties in becoming
Open-label minutes at baseline to 392±95 minutes at wide awake in the morning often or very often, and 13
study in day 42 (not statistically significant). patients complained of daytime sleepiness often or very
adults to often. By day 42 these problems were reported in two
• Time to both sleep onset and REM onset
assess the patients.
improved significantly by day 7.
effects of
• No significant changes from baseline in stage • This small study shows that agomelatine can increase
agomelatine
on sleep. 1 or 2 sleep, any aspect of the REM sleep, sleep efficiency and slow-wave sleep, as shown by the
Patients with Sleep cycle the time of sleep onset and the delta power lengthening of stage 3-4 sleep and does not suppress
Agome- ratio (indicating improvement in NREM) by REM sleep, which can be poor in patients with depression,
sleep ap- analysed by
latine day 42. Trend towards an improvement in stage 1 or 2 sleep and time to sleep onset. Dose-
noea, shift poly-
25mg REM latency (uncorrected value) by day 42. dependent suppression of REM sleep has been seen with
workers and somnogra-
(n=15) for tricyclic antidepressants, SSRIs and venlafaxine. It has
post- phy, on six • Statistically significant improvements were
42 days. been thought that the increase in the delta power ratio,
menopausal nights. seen at day 42 in the intra-sleep awakening
women were time, decreasing from 48±31 minutes to seen with e.g. sertraline and amitriptyline, could be due
excluded. 29±27 minutes; the sleep efficiency (total to their REM suppression effect, leading to a delay in the
Patients sleep time: total sleep period ratio), increas- first REM sleep, but this is not the case for agomelatine.
scored at ing from 88% to 93% and stages 3-4 slow- • The authors of this study state that agomelatine improves
least 20 on wave sleep increasing from 15.9% of the the deficiency of the homeostatic system of sleep regula-
the HAMD total sleep period to 19.4%, a mean increase tion, by improving slow wave sleep and activity. Further
scale.16 of 14 minutes. SWS started to improve as controlled studies investigating sleep and daytime alert-
early as day 7. ness would be warranted.
• Data comes from a conference abstract.
• In animal models agomelatine has been shown to resyn-
chronise altered circadian rhythms.
Relative am- • Relative amplitude is based on average activity level dur-
Randomised
plitude (RA) ing the 10 most active and 5 least active hours of a 24
6 week
of rest/ hour period.
study as-
activity cycle, • The mean RA was stable between days 0-7 in the agome-
sessing the Agome- • Sleep latency (how quickly to fall asleep),
sleep latency, latine group and decreased in the sertraline group. The
rest-activity latine 25- changes from baseline: 22.5 to 18.9 min-
sleep effi- mean RA increased in the sertraline group from day 7,
circadian 50mg utes, agomelatine (p<0.0001), vs. 23.48 to
ciency. and from day 14 there was no significant difference be-
rhythm us- (n=154) or 27.75 minutes, sertraline.
ing wrist sertraline tween the groups.
Sleep efficiency (total sleep time: total sleep
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Secondary •
actigraphy in 50-100mg period): 78.85% agomelatine (p<0.0001) • Sleep efficiency increased at each assessment point with
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endpoint:
patients with (n=159). vs. 76.70% sertraline. agomelatine, yet with sertraline it alternated between
change in
a HAMD decreasing and increasing: a longer study may show no
HAMD score.
score difference between the two treatments. Improvements in
(see Short
≥22.14;15 both measurements were seen as early as after one week
term studies)
of treatment with agomelatine.
• Most commonly reported adverse events were dry mouth,
headache, diarrhoea and fatigue. More patients discon-
June 2009
• The comparison between agomelatine and venlafaxine on
Agomelatine
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with agomelatine (71.6%) compared with venlafaxine
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(66.7%). Bias from the initial focus on subjective sleep
parameters in favour of agomelatine cannot be ruled out.6
LSEQ: Leeds Sleep Evaluation Questionnaire, assessed using a visual analogue scale. These are very subjective and are best for compar-
ing changes within individuals, rather than between individuals. Clinical relevance is a 10mm or greater change from baseline. Note all
patients start with a baseline rating of 50 on the LSEQ scale – from this start point improvement or worsening of symptoms is determined.
Agomelatine Page 19
Sleep diary
• Completed every morning to the week 3 visit recording: times of light off, wake-up and get-
ting up, sleep onset latency and number of nocturnal awakenings.
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As already stated, NICE recommends an SSRI as first line treatment for moderate to severe depression.
The budget impact model has been based on agomelatine use in second-line or later treatment for de-
pression, with agomelatine taking a 10% share of the current patients who fall into this category. Below
is a breakdown of the cost per 100,000 population if agomelatine is used as a second-line or later treat-
ment for depression, for year 1.
For years 2 and 3, the number of patients treated with agomelatine is expected to rise.
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28x20mg: £1.26
Citalopram‡ 20mg, increased to 60mg daily
28x40mg: £1.44
30x20mg: £1.02
Fluoxetine‡ 20mg, increased to 60mg daily
30x60mg: £55.73
28x20mg: £2.84
Paroxetine‡ 20mg, increased to 50mg daily
28x30mg: £6.21
28x50mg: £1.36
Sertraline‡ 50mg, increased to 100mg daily
28x100mg: £1.67
Reference List
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en6.pdf on 18/03/09.
(7) Loo H, Hale A, D'haenen H. Determination of the dose of agomelatine, a melatoninergic agonist
and selective 5-HT2c antagonist, in the treatment of major depressive disorder: a placebo-
controlled dose range study. Int Clin Psychopharmacol 2002; 17(5):239-247.
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(8) Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major de-
pressive disorder. Eur Neuropsychopharmacol 2006; 16(2):93-100.
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30 August - 3 September: 2008
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lapse in patients with major depressive disorder over 10 months. Poster presentation. Euro-
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gust - 3 September: 2008
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disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with
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THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES.
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The LNDG would like to thank Guy Goodwin, Professor of Psychiatry, Waneford Hospital, Oxford;
Karen Harvey, Senior Lead Pharmacist, Mental Health, Charing Cross Hospital; Trudi Hilton, Chief
Pharmacist, West London Mental Health Trust; Svetlana Jokic, Senior Mental Health Pharmacist, Im-
perial College Healthcare, and David Taylor, Professor of Psychopharmacology, Kings College, for
their comments on the initial draft of the review. Servier Laboratories has commented on the final
review.
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Agomelatine 25mg
Relapse rates 25.9%, p=NS 23.5%
for 8 weeks then
HAMD total score,
agomelatine (n=187)
time to relapse.
or placebo (n=180) Relapse rates in pts with 21.3%, p=0.046 at
31.3%
for 26 weeks. EPAR6 more severe depression week 52
Agomelatine 25-
50mg (n=165) or Relapse over 6 months 21.7%, p<0.0001 46.6%
placebo (n=174) for Relapse: HAMD
24 weeks plus 20 ≥16
weeks. Relapse over 10 months 23.9%, p<0.0001 49.9%
Goodwin et al10l33
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Appendix 2: Results of the improvements in subjective sleep study, agomelatine vs. venlafaxine.12
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